Levodopa reportedly inhibits insulin action in skeletal muscle. Here we show that C2C12 myotubes produce levodopa and that insulin-stimulated glucose transport is enhanced when endogenous levodopa is depleted. Exogenous levodopa prevented the stimulation of glucose transport by Insulin (P < 0.05) and Increased cAMP concentrations (P < 0.05). The decrease in Insulin-stimulated glucose transport caused by levodopa was attenuated by propranolol (a β-adrenergic antagonist) and Prevented by NSD-1015 (NSD), an inhibitor of DOPA decarboxylase (DDC; converts levodopa to dopamine). Propranolol and NSD both prevented levodopa-related increases in [cAMP]. However, the effects of levodopa were unlikely to be dependent on the conversion of levodopa to catecholamines because we could detect neither DDC in myotubes nor catecholamines in media after incubation of myotubes with levodopa. The data suggest the possibility of novel autocrine β-adrenergic action in C2C12 myotubes in which levodopa, produced by myotubes, could have hormone-like effects that impinge on glucose metabolism.
BoydAEIII, LebovitzHE, FeldmanJM.Endocrine function and glucose metabolism in patients with Parkinson's disease and their alteration by L-Dopa. J Clin Endocrinol Metab33:829-837, 1971.
SirtoriCR, BolmeP, AzamoffDL.Metabolic responses to acute and chronic L-dopa administration in patients with Parkinsonism. New Engl J Med287:729-733, 1972.
4.
HakansonR, LundquistI, RerupC.On the hyperglycaemic effect of DOPA and dopamine. Eur J Pharmacol1:114-119, 1967.
5.
SmithJL, JuJS, SahaBM, RacetteBA, FisherJS.Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle. J Appl Physiol97:2339-2346, 2004.
6.
SchubertD, TarikasH, LaCorbiereM.Neurotransmitter regulation of adenosine 3′,5′-monophosphate in clonal nerve, glia, and muscle cell lines. Science192:471-473, 1976.
7.
MisuY, GoshimaY, UedaH, OkamuraH.Neurobiology of L-DOPAergic systems. Prog Neurobiol49:415-454, 1996.
8.
MisuY, YueJL, GoshimaY.L-DOPA systems for blood pressure regulation in the lower brainstem. Neurosci Res23:147-158, 1995.
9.
GoshimaY, KuboT, MisuY.Biphasic actions of L-DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices. Br J Pharmacol89:229-234, 1986.
10.
LangCH.Beta-adrenergic blockade attenuates insulin resistance induced by tumor necrosis factor. Am J Physiol264:R984–R991, 1993.
11.
ZierathJR, HandbergA, TallyM, Wallberg-HenrikssonH.C-peptide stimulates glucose transport in isolated human skeletal muscle independent of insulin receptor and tyrosine kinase activation. Diabetologia39:306-313, 1996.
JueT, RothmanDL, ShulmanGI, TavitianBA, DeFronzoRA, ShulmanRG.Direct observation of glycogen synthesis in human muscle with 13C NMR. Proc Natl Acad Sci USA86:4489-4491, 1989.
14.
ShulmanGI, RothmanDL, JueT, SteinP, DeFronzoRA, ShulmanRG.Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med322:223-228, 1990.
15.
SomwarR, KimDY, SweeneyG, HuangC, NiuW, LadorC, RamlalT, KlipA.GLUT4 translocation precedes the stimulation of glucose uptake by insulin in muscle cells: potential activation of GLUT4 via p38 mitogen-activated protein kinase. Biochem J359:639-649, 2001.
JuJS, SmithJL, OppeltPJ, FisherJS.Creatine feeding increases GLUT4 expression in rat skeletal muscle. Am J Physiol Endocrinol Metab288:E347–E352, 2005.
22.
AritaDY, Di MarcoGS, SchorN, CasariniDE.Purification and characterization of the active form of tyrosine hydroxylase from mesangial cells in culture. J Cell Biochem87:58-64, 2002.
23.
Di MarcoGS, Naffah-Mazzacoratti Md MdaG, VioCP, Dos SantosOF, SchorN, CasariniDE.Mesangial cells are able to produce catecholamines in vitro. J Cell Biochem89:144-151, 2003.
24.
SakamotoK, HirshmanMF, AschenbachWG, GoodyearLJ.Contraction regulation of Akt in rat skeletal muscle. J Biol Chem277:11910-11917, 2002.
25.
LiSW, LinTS, MinteerS, BurkeWJ.3,4-dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: possible role in Parkinson's disease pathogenesis. Brain Res Mol Brain Res93:1–72001.
26.
McCulloughLA, WestfallTC.Neuropeptide Y inhibits depolarization-stimulated catecholamine synthesis in rat pheochromocytoma cellsEur J Pharmacol287:271-277, 1995.
27.
TabataI, SchluterJ, GulveEA, HolloszyJO.Lithium increases susceptibility of muscle glucose transport to stimulation by various agents. Diabetes43:903-907, 1994.
28.
GulveEA, CarteeGD, ZierathJR, CorpusVM, HolloszyJO.Reversal of enhanced muscle glucose transport after exercise: roles of insulin and glucose. Am J Physiol259:E685–E691, 1990.
29.
TresederSA, RoseS, SummoL, JennerP.Commonly used L-amino acid decarboxylase inhibitors block monoamine oxidase activity in the rat. J Neural Transm110:229-238, 2003.
30.
HunterLW, RorieDK, TyceGM.Inhibition of aromatic L-amino acid decarboxylase under physiological conditions: optimization of 3-hydroxybenzylhydrazine concentration to prevent concurrent inhibition of monoamine oxidase. Biochem Pharmacol45:1363-1366, 1993.
31.
ThongFS, DeraveW, KiensB, GrahamTE, UrsoB, WojtaszewskiJF, HansenBF, RichterEA.Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise. Diabetes51:583-590, 2002.
32.
GoshimaY, NakamuraS, MisuY.L-dopa facilitates the release of endogenous norepinephrine and dopamine via presynaptic beta 1- and beta 2-adrenoceptors under essentially complete inhibition of L-aromatic ammo acid decarboxylase in rat hypothalamic slicesJpn J Pharmacol53:47-56, 1990.
33.
TedroffJM.The neuroregulatory properties of L-DOPA: a review of the evidence and potential role in the treatment of Parkinson's diseaseRev Neurosci8:195-204, 1997.
34.
NishihamaM, MiyamaeT, GoshimaY, OkumuraF, MisuY.An L-dopaergic relay from the posterior hypothalamic nucleus to the rostral ventrolateral medulla and its cardiovascular function in anesthetized rats. Neuroscience92:123-135, 1999.
35.
GoshimaY, NakamuraS, MisuY.L-DOPA facilitates the release of endogenous norepinephrine and dopamine via presynaptic β1- and β2-adrenoceptors under essentially complete inhibition of L-aromatic amino acid decarboxylase in rat hypothalamic slices. Jpn J Pharmacol53:47-56, 1990.
36.
GoshimaY, NakamuraS, MisuY.L-dihydroxyphenylalanine methyl ester is a potent competitive antagonist of the L-dihydroxyphenylalanine-induced facilitation of the evoked release of endogenous norepinephrine from rat hypothalamic slices. J Pharmacol Exp Ther258:466-471, 1991.
37.
SlominskiA, PausR.Towards defining receptors for L-tyrosine and L-dopa. Mol Cell Endocrinol99:C7–C11, 1994.
38.
KoenigH, GoldstoneA, LuCY.Androgens regulate mitochondrial cytochrome c oxidase and lysosomal hydrolases in mouse skeletal muscle. Biochem J192:349-353, 1980.
YenTT, GillAM, FrigeriLG, BarshGS, WolffGL.Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J8:479-488, 1994.
41.
SmithSR, Gawronska-KozakB, JanderovaL, NguyenT, MurrellA, StephensJM, MynattRL.Agouti expression in human adipose tissue: functional consequences and increased expression in type 2 diabetes. Diabetes52:2914-2922, 2003.
KimS, JeeK, KimD, KohH, ChungJ.Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1. J Biol Chem276:12864-12870, 2003.
44.
LeeAD, HansenPA, SchluterJ, GulveEA, GaoJ, HolloszyJO.Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle. Am J Physiol273:0082-0087, 1997.
